Upcoming events – US approvals due for Eisai and Biomarin, and data for Madrigal

Welcome to your weekly digest of approaching regulatory and clinical readouts. Eisai and Merck’s Lenvima has a US action date by the end of May for use in first-line liver cancer, a valuable indication, but one threatened by immunotherapy.

Also due before the US regulators is Biomarin’s second phenylketonuria product, Pegvaliase, which has shown better efficacy than its older drug Kuvan. Lastly, Madrigal Pharmaceuticals is due to report data on its Nash project MGL-3196 that will give the first idea of an impact on fibrosis.

Liver target

Eisai and Merck’s VEGFr kinase inhibitor Lenvima is due before the FDA by the end of this month in a new indication, first-line unresectable liver cancer, a use where it gained Japanese approval in March.

The filings are based on the pivotal Reflect trial, which tested Lenvima versus Bayer’s Nexavar – currently the only drug approved in the US for unresectable liver cancer. Lenvima met non-inferiority on the primary endpoint, with an overall survival of 13.6 months versus 12.3, and also showed significant benefits over Nexavar in terms of PFS, time to progression and response rate (Therapy focus – Opdivo and Livatag could add to liver cancer options, July 3, 2017).

In the US Lenvima is sold for advanced renal cancer and locally recurrent or metastatic thyroid cancer. By 2024 global sales are forecast to reach $2.2bn, according to EvaluatePharma sellside consensus, with 58% of this coming from liver cancer. The drug is expected to be the market leader in liver cancer by 2024.

However, Bristol-Myers Squibb’s Opdivo is a fierce competitor: it is the only anti-PD-(L)1 drug approved in liver cancer, in second-line use. Opdivo is expected to move into the first-line setting if the Checkmate-459 trial is positive; results are due by the end of the year.

Top-selling liver cancer drugs by 2024

Global indication sales ($m)

Project

Company

2018e

2024e

Indication status

Lenvima

Eisai/Merck & Co

184

1,290

Marketed in Japan, unresectable cancer, PDUFA in US May

Opdivo

Ono Pharmaceutical/Bristol-Myers Squibb

11

660

Marketed 2nd line, after Nexavar

BLU-554

Blueprint Medicines

-

518

Phase I

Resminostat

4SC

-

491

Phase II

Cabometyx

Exelixis/Ipsen

11

349

Filed 2nd line advanced

Stivarga

Bayer

73

346

Marketed 2nd line, after Nexavar

Nexavar

Bayer

792

241

Marketed unresectable

ThermoDox

Celsion

-

124

Phase III

ENMD-2076

Casi Pharmaceuticals

-

118

Phase II

Derazantinib

Arqule

-

69

Phase III

Source: EvaluatePharma.

Biomarin’s second PKU drug

Biomarin’s Pegvaliase will be approved or rejected by the FDA by May 25. The project is used to reduce phenylalanine levels in patients with phenylketonuria (PKU), a rare inherited condition where accumulation of phenylalanine can cause mental disabilities and seizures.

Approval for Pegvaliase would make it Biomarin’s second drug for PKU. Its first, Kuvan, was approved in the US in 2007, but only works in a subset of patients and must be accompanied by a strict low-protein diet to keep phenylalanine levels down.

Pegvaliase’s pivotal phase III study, Prism-2, showed significant reductions in blood phenylalanine levels versus placebo. The reductions were more profound than had been seen with Kuvan, and were achieved without the dietary restrictions.

However, there were mixed results around cognition, with most endpoints missing significance and some even showing trends in favour of placebo (BioMarin stumbles ahead of second phenylketonuria filing, March 21, 2016). Notably, Kuvan does not have cognition improvements on its label either.

In terms of safety, Prism-2 patients treated with Pegvaliase experienced a higher rate of hypersensitivity adverse events compared with placebo, at 39% versus 14%. The company has noted that reactions occurred early and were controlled by slow titration and use of pre-medications such as antihistamines.

Pegvaliase’s approval looks likely since there are so few treatment options. 2024 global forecasts for Pegvaliase sit at $370m, according to consensus from EvaluatePharma. Kuvan sold $408m last year, and sales are forecast to fall to $166m by 2024.

Biomarin expects Pegvaliase to become the treatment of choice for adults. In Prism-2 it was self-administered as a subcutaneous injection. Oral Kuvan will likely continue to be the standard for children. The company has previously said it will wait until it has Pegvaliase approved in adults before starting a paediatric programme.

Study

Trial ID

Details

Prism-1/Prism301

NCT01819727

Treatment introduction study

Prism-2/Prism302

NCT01889862

Pivotal study

36-week test

Madrigal Pharmaceuticals is due to report 36-week liver biopsy data on its Nash therapy MGL-3196 at the end of May, with the phase II study in 125 subjects providing the first biopsy data with MGL-3196.

Improvement in liver fibrosis remains a tough standard to meet in Nash, and the upcoming biopsy data are important. The results will also allow for correlations with assessments using noninvasive imaging and biomarker measurements.

The β-selective thyroid hormone receptor agonist is Madrigal’s lead asset, and is also being tested in heterozygous familial hypercholesterolaemia. 2024 consensus forecasts show MGL-3196 selling just over $1bn, according to EvaluatePharma; 89% of this figure is assigned to Nash.